Despite numerous studies on the impact of viral diversity, HIV-l-specific immune responses and host factors on disease progression, we still do not have a firm understanding of the long-term pathogenesis of HIV-I. The ability of primary HIV-1 strains to replicate in macrophages correlates with the stage of disease progression, suggesting that enhanced M-tropism of HIV-1 is an important factor contributing to HIV-1 disease progression. We predict that enhanced M-tropism results from adaptive evolution of HIV-1 Env species during the course of infection to variants better able to utilize low levels of CD4 and/or coreceptor for entry and cell to cell fusion, resulting in cytopathic HIV-1 variants able to cause CD4+ T-cell depletion. To address this, we will isolate and characterize longitudinal sets of primary HIV-1 strains from individuals during the course of HIV-1 infection. Understanding the molecular basis of enhanced M-tropism will provide further insights into HIV-1 pathogenesis, which is vital for the development of new inhibitors for the treatment of HIV-1 infection.